Last large HIV vaccine trial fails

  • by Liz Highleyman, BAR Contributor
  • Wednesday December 13, 2023
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PrEPVacc chief investigator Dr. Pontiano Kaleebu. Photo: PrEPVacc
PrEPVacc chief investigator Dr. Pontiano Kaleebu. Photo: PrEPVacc

The last large HIV vaccine study has been halted ahead of schedule after researchers determined "there is little or no chance of the trial demonstrating vaccine efficacy in preventing HIV acquisition," according to a December 6 announcement. Leaders of the PrEPVacc trial shared the news at the International Conference on AIDS and STIs in Africa, held last week in Zimbabwe.

While this outcome is disappointing, the International AIDS Society stressed the need to step up HIV vaccine research and development.

"We cannot and will not lose hope that the world will have an effective HIV vaccine that is accessible by all who need it, anywhere," said IAS Executive Director Birgit Poniatowski. "A vaccine remains one of our most powerful tools to reach and change the lives of vulnerable communities and key populations in the most affected parts of the world."

The PrEPVacc trial, testing two vaccine regimens along with two different PrEP pills, enrolled more than 1,500 men and women at risk for HIV in South Africa, Tanzania, and Uganda. The participants will not receive any more vaccine doses, but they will be followed for additional safety data collection. The oral PrEP component of the study is ongoing.

The trial's early discontinuation does not put an end to HIV vaccine research, but it does suggest that more sophisticated approaches will be needed.

"We have come so far in our HIV prevention journey, but we must look to a new generation of vaccine approaches and technology to take us forward again," stated PrEPVacc chief investigator Dr. Pontiano Kaleebu of the Medical Research Council/Uganda Virus Research Institute and London School of Hygiene and Tropical Medicine Uganda Research Unit. "We must also look to a new generation of leaders. We set up PrEPVacc to grow our capacity in Africa to do future trials ourselves and to develop those who will lead them here in Africa."

A history of disappointments

Only one large vaccine study — the RV144 trial in Thailand — has shown any effectiveness for HIV prevention. That trial tested a vaccine called AIDSVAX that contains HIV's gp120 envelope protein plus a second vaccine that delivers DNA instructions for HIV proteins. In 2009, researchers reported that this regimen reduced new infections by 31%.

But later studies evaluating this kind of traditional vaccine approach did not see a similar benefit.

The Uhambo trial tested a DNA vaccine plus another vaccine containing gp120 proteins. It was halted in 2020 after early results showed that it did not prevent HIV infection. Two large phase III vaccine trials, Imbokodo and Mosaico, tested a vaccine that uses an adenovirus vector to deliver antigens from multiple HIV strains plus different booster vaccines. As the Bay Area Reporter previously reported, Imbokodo was halted in August 2021 after the vaccine regimen did not reduce the risk of HIV acquisition for young women in Africa. Likewise, Mosaico was stopped this past January because it failed to protect gay and bisexual men and transgender women in North and South America and Europe.

That left PrEPVacc as the only ongoing large vaccine trial. The study used an approach similar to the one that showed promise in the RV144 trial. Participants were randomly assigned to receive AIDSVAX plus a DNA vaccine, these two vaccines plus a third vaccine that uses a modified poxvirus vector to deliver HIV DNA, or placebo injections.

In addition, the study compared two PrEP pills, Descovy (tenofovir alafenamide/emtricitabine) and Truvada (tenofovir disoproxil fumarate/emtricitabine). Truvada is approved as an HIV prevention option for all populations, but Descovy is not yet approved for cisgender women, trans men, and others exposed to HIV via vaginal sex due to inadequate data. PrEPVacc, which enrolled nearly 90% women, aims to fill that research gap.

As of October, more than 1,000 participants had received the full vaccine regimen and most of them also received one of the PrEP pills. Reviewing interim data in November, the study's independent data monitoring committee found no safety concerns. However, based on the early findings, they determined that the trial would likely be unable to show that the vaccine can prevent HIV. Full study results are expected in the second half of 2024.

Some experts and advocates think this is not surprising, because PrEP pills alone are so effective that it's difficult to tell if vaccines provide additional protection. Ethics require study investigators to offer participants the best existing prevention tools, so experimental vaccines can no longer be pitted against just a placebo.

PrEPVacc appears to be "the last roll of the dice" for traditional HIV vaccines, study coordinator Dr. Jonathan Weber of Imperial College London, told CNN earlier this year.

"We do clinical trials because we don't know the answer to questions. It was important to find out whether the combination vaccine regimens in PrEPVacc, developed over 20 years, should be ruled out or further developed for preventing HIV," Weber added in last week's announcement. "While we await the final results and analysis of individual products, I believe that our interim result puts this generation of putative HIV vaccines to bed."

New approaches needed

After repeatedly failing to show that traditional vaccines can prevent HIV, researchers are now exploring more sophisticated strategies.

Some experts think a successful vaccine will need to trigger the production of broadly neutralizing antibodies that can recognize multiple strains of HIV. One approach, known as germline targeting, uses a series of vaccines in a stepwise manner to encourage the development of specialized B cells that can produce broadly neutralizing antibodies. Researchers hope to speed up the process by employing the same mRNA technology used for COVID-19 vaccines. Taking a different approach, Vir Biotechnology is testing an experimental vaccine designed to produce T cells that recognize HIV.

Early results from small studies of these and other strategies look promising, but much work remains to be done before they can be tested in large human trials, experts said.

"The PrEPVacc outcome underscores yet again that the science of HIV vaccine development is extremely challenging," said AVAC Executive Director Mitchell Warren. "Now is not the time to step back from vaccine research. There are several promising strategies in early-stage research that must continue, along with research for other HIV prevention options. We will not end HIV without ensuring that everyone who is vulnerable to HIV infection has a choice of effective and desirable prevention options."

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